Lyme disease is the most common arthropod-borne infection in the United States. Over 100,000 cases have been reported to date. The disease is a multisystem disorder with dermatologic, neurologic and rheumatologic manifestations. The spirochete, Borrelia burgdorferi, is the causative agent. Central to the disease process, in the absence of a demonstrated toxin, is the interaction between the microorganism and host cells. In order to examine whether cells undergo detectable, cytopathic changes in response to spirochetes, we have undertaken to assess possible interactions between B. burgdorferi and both primary or cultured human cells in vitro. Cytoadhesive receptors expressed on cell surfaces are essential for cell-cell interaction and adhesion to the extracellular matrix. Many microorganisms have evolved the ability to use these surface receptors, called integrins, to bind and then to invade host cells. This ability often becomes an important virulence determinant. A broadly applicable method was developed in which scanning electron microscopy is used to sensitively and specifically assess this important binding potential under carefully controlled conditions. The rapid assay which uses commercially available, genetically engineered cytoadhesive molecules and site specific competitive inhibitors in a convenient filter/cell culture insert format may be used to yield either qualitative and/or quantitative data. Furthermore, the specimens appear suitable for high resolution SEM examination as well following the initial assay. The efficient use of the fibronectin, but not the vitronectin or laminin, cellular binding receptor by Borrelia burgdorferi was demonstrated using the SEM assay method. Gentle disruption and washing of bound spirochetes with N-lauroylsarcosine followed by detergent elution and polyacrylamide gel electrophoresis of bound polypeptides revealed a unique, limited subset of binding components. Borrelial major outer surface protein A (OspA) was most prominent among them.